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Preeclampsia

Preeclampsia. Hypertension & proteinuria in last trimester of pregnancy Complicates 2-3 % pregnancies Requires placenta (even if no fetus; hydatidiform pregnancy) Remits post-partum Placenta is frequently abnormal with ischemic/hypoperfusion lesions

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Preeclampsia

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  1. Preeclampsia • Hypertension & proteinuria in last trimester of pregnancy • Complicates 2-3 % pregnancies • Requires placenta (even if no fetus; hydatidiform pregnancy) • Remits post-partum • Placenta is frequently abnormal with ischemic/hypoperfusion • lesions • In severe PE, there is micro-angiopathy and endothelial • dysfunction with many target organs potentially • involved: liver, kidney, CNS, etc.

  2. Pathogenesis of Preeclampsia “Disease of theories"

  3. Poor Placentation and Preeclampsia

  4. Placental Vascular Pathology in Preeclampsia Normal Preeclampsia “Placental vascularinsufficiency”

  5. Glomerular Endotheliosis Control Preeclampsia

  6. Abnormal Placenta and Placental Factors • neurokinin B Nature. 2000 Jun 15;405(6788):797-800 • thromboplastin Nature. 1963 Sep 14;199:1105-6 • magnesium deficiency Science. 1983 Jul 22;221(4608):376-8 • adrenomedullinLancet. 1997 Nov 29;350(9091):1600

  7. EPO and sVEGFR1 (sFlt1) in Amniotic Fluid Vuorela et al, 2000

  8. Annual Reviews

  9. Plasma sFlt1 in Pregnancy Levine et al 2004

  10. In vivo Effects of sFlt1 Maynard et al, 2003

  11. Cytotrophoblast Response to Hypoxia Nagamatsu et al 2004

  12. Utero-placental Ischemia in Primates Placental perfusion reduced by ~ 30-50% Makris et al, KI 2007

  13. Utero-placental Ischemia in Primates

  14. Preeclampsia • Increased in some factors that are activated during hypoxia • Can be induced by reduction of placental blood flow • Hence, either there is ischemia (with appropriate hypoxic • response) or there is an abnormality in the • hypoxia-regulated response

  15. Oxygen Sensing HIF1α α α α VEGF

  16. 2-Methoxyestradiol Inhibits EC Growth, Angiogenesis and Tumor Growth Fibroblats EC Fotsis et al, 1994

  17. 2-Methoxyestradiol CYP450 COMT - pM in control Plasma - nM in plasma of pregnancy - μM in ovaries & tissues with high [estradiol]

  18. Catechol-O-methyl Transferase

  19. 2-Methoxyestradiol Inhibits HIF1α α-tubulin HIF1α Mabjessh et al 2003

  20. 2-Methoxyestradiol and HIF

  21. COMT-/-

  22. COMT in Placenta

  23. Placenta

  24. Placenta Thrombosis arterial lumen Eosin+ deposition +/+ -/- +/+ 2/56 32/64 -/- -/- + 2ME -/- +2ME

  25. Placenta +ME IgM vWF

  26. Blood Pressure

  27. Non-pregnant Blood Pressure

  28. Proteinuria

  29. Kidney WT WT+Ro41-0960 COMT-/- COMT-/- + ME EC swelling, detachment and vacualization (“endotheliosis”)

  30. Placental Hypoxia WT COMT-/- COMT-/- + ME WT -/- -/- + ME

  31. Placental HIF1α WT COMT-/- COMT-/- + ME SP, spongiotrophoblast layer

  32. Placental HIF1α WT -/- -/- + ME

  33. Plasma sFLT-1

  34. Plasma Catecholamines WT + MAO inhibitor

  35. Placental Vasodilators RT-PCR Western

  36. Inflammatory Mediators

  37. Decidual IFN-γ and NK Cells IFN-γ NK Cells NKp46+ CD3-

  38. 2-Methoxyestradiol Effects in Cytotrophoblast Cell Line microtubule disruption Tubulin

  39. Human Pregnancy

  40. 2-Methoxyestradiol and COMT in Human Pregnancy Plasma 2-ME Placental COMT

  41. Summary • 2-methoxyestradiol inhibits HIF1α • Placenta expresses catechol-O-methyl transferase and 2-ME increases • during pregnancy • COMT KO and COMT inhibitors cause pre-eclampsia • 2-ME prevents pre-eclampsia in COMT KO mice; thus, PE in these mice • its unlikely due to excess catecholamines and vasoconstriction • Women with PE have low plasma levels of 2-ME and lower COMT protein • in their placenta; 2-ME may provide a therapy for pre-eclampsia

  42. Proposed Model

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